Molecular Testing and Tumor Sidedness in CRC

Bassel F. El-Rayes, MD:In my practice, I order molecular testing at diagnosis. Molecular testing in colon cancer has a huge impact on the management plan, and therefore, having the information early on in the course of the disease is key. The minimum amount of molecular testing that we need to manage a patient would be testing for microsatellite instability. That is number 1. Number 2 is an extendedRASmutational panel. And number 3 isRAFmutations. This is the minimum amount of molecular testing that we need. In my practice, I tend to do next-generation sequencing because that gives me those 3 minimum things that we need in addition to a whole number of other genes that could have an impact down the line in the management of these patients.

RAStesting is needed for all patients with colon cancer regardless of the sidedness of the tumor. Although, in right-sided tumors, the impact ofRAStesting is not for the frontline setting. It may have an impact on management in the second-line or third-line setting. So that’s why I believe everybody with colon cancer needsRAStesting.

NTRKfusions are present in a small proportion of patients with colon cancer. However, when we identify patients withNTRKmutations, there’s the option of doing targeted therapies that have shown to be very effective in that small subset of patients. And that’s one of the reasons why doing a more comprehensive next-generation sequencing approach would provide the information about uncommon mutations, likeNTRK,early on in the course of the management of these patients and allow us to develop a management plan that will incorporate those drugs in the first line, second line, or third line.

For a long time, we’ve known that tumor sidedness has an impact on the outcome of patients independent of the treatment that they receive. And in that sense, it is a prognostic indicator. Patients with right-sided tumors tend to have a worse outcome than patients with left-sided tumors. In addition to its prognostic value, sidedness of the tumor has an impact on responsiveness to certain therapies, specifically EGFR inhibitors. And in that sense, it is a predictive marker. We know that patients who have right-sided tumors should be treated with chemotherapy plus bevacizumab in the up-front setting and not chemotherapy plus an EGFR inhibitor in the up-front setting, regardless ofKRASandBRAFmutational status. For right-sided tumors, we should start with bevacizumab as a targeted drug. And in that role, sidedness of the tumor is predictive.

Transcript edited for clarity.

Case: A 75-Year-Old ManWithRight-Sided mCRC

Initial presentation

• A 75-year-old Caucasian man presented to his PCP with rectal bleeding, fatigue, weight loss, and constipation

Clinical workup

• Colonoscopy: fungating mass in the ascending colon
• Biopsy: invasive, poorly differentiated adenocarcinoma
• Imaging: CT scan of the chest/abdomen/pelvis showed multiple small liver lesions including a 3-cm mass in right lobe
• Molecular testing on tissue biopsy:
  • KRAS, RAS, andBRAFWT
  • Microsatellite-stable
• ECOG PS 1

Treatment

• Patient underwent a diverting colostomy without complication
• He was started on FOLFOX and bevacizumab
• Follow up imaging at 3, 6, and 9 months showed a partial response
• He was continued on bevacizumab and underwent capecitabine maintenance
• Imaging at 12 months showed 2 new liver lesions (1.2 cm and 3.4 cm)